The present invention generally relates to processes for producing 2-halo-nicotinic acid derivatives and precursors thereto. In a highly preferred aspect, the invention relates to a synthesis of 2-halo-nicotinic acid derivative compounds which includes reacting a 2-halonitrile with an .alpha.,.beta.-unsaturated aldehyde or ketone to give a 4-halo-4-cyano carbonyl compound, followed by a cyclocondensation reaction to afford the 2-halo-nicotinic acid derivative. The 2-halonitrile can optionally be prepared in situ by reacting 2,2-dihalonitrile with the parent nitrile.
As background, 2-halo-nicotinic acid and its derivatives are highly useful in many organic synthetic applications, and in one facet represent an important class of agricultural and pharmaceutical intermediates. For example, 2-chloronicotinic acid and its amides have been the subject of much patent literature (See e.g. Chiang et al., EP 323,881 (1989), Cramp et al., U.S. Pat. No. 4,618,366 (1986), Gutman, U.S. Pat. No. 4,251,263 (1981), Oda et al., U.S. Pat. No. 4,840,959 (1989), and Hoffmann et al., U.S. Pat. Nos. 3,466,373 (1968) and 3,415,834 (1969)).
Prior known methods of preparing 2-halo-nicotinic acid derivatives typically involve manipulation of a functional group on an existing pyridine ring. For example, Lisac, Spanish Patent No. ES 501,988 (1981) discloses the preparation of 2-chloronicotinic acid by oxidation of 2-chloro-3-methylpyridine at 190.degree. to 210.degree. C. in the presence of a mixture of sulfuric acid and nitric acid. Japanese Patent: Kokai 58-213760 (published Dec. 12, 1983) and Haga et al., U.S. Pat. No. 4,504,665 (1985) describe the synthesis of 2-chloronicotinic acid by hydrolysis of 2-chloro-3-trichloromethylpyridine. Both of these methods harbor significant disadvantages, including that they generally require starting materials that are difficult to selectively prepare.
2-Chloronicotinitrile has been also prepared by treating nicotinamide N-oxide with a mixture of phosphorous pentachloride and phosphorous oxychloride, as described by Taylor et al., J. Org. Chem., 1954, 19, 1633. Similar N-oxide-based preparations of 2-chloronicotinic acid are described by Richter et al., Hungarian Patent No. 221161 (1982), Said, U.S. Pat. No. 4,144,238 (1979) and Naoi et al., Japanese Patent: Kokai 59-144759 (published Aug. 18, 1984). However, these N-oxide-based approaches are complicated by contamination by regioisomers (mainly 6-chloro derivative) and operational difficulties.
Regioselective synthesis of 2-halo-nicotinic acid derivatives by ring synthesis has also been investigated to some extent. Bryson et al., J. Org. Chem., 1974, 39, 3436 and Japanese Patent: Kokai 55-76863 (published Jun. 10, 1980) describe cyclocondensation reactions of a dienyl ethers. Chiang et al., EP 323,881 (1989) describe a similar process for preparing N,N-dialkyl-2-chloro-nicotinamide. However, the high cost of starting materials for these processes has limited the successful application of these routes to commercial production, Bryson et al., J. Org. Chem., 1976, 41, 2067 and Schroder, U.S. Pat. No. 4,987,232 (1991) describe a similar processes from dienamines. These also involve the use of prefabricated intermediates such as vinyl ether and enamines.
Despite these previous efforts, there remains a need for a simple, efficient process for preparing 2-halo-nicotinic acid derivatives and precursors thereto from readily available starting materials. The present invention addresses this need.